title: Ebselen treatment prevents islet apoptosis, maintains intranuclear Pdx-1 and MafA levels, and preserves β-cell mass and function in ZDF rats.
abstract: We reported earlier that β-cell-specific overexpression of glutathione peroxidase (GPx)-1 significantly ameliorated hyperglycemia in diabetic db/db mice and prevented glucotoxicity-induced deterioration of β-cell mass and function. We have now ascertained whether early treatment of Zucker diabetic fatty (ZDF) rats with ebselen, an oral GPx mimetic, will prevent β-cell deterioration. No other antihyperglycemic treatment was given. Ebselen ameliorated fasting hyperglycemia, sustained nonfasting insulin levels, lowered nonfasting glucose levels, and lowered HbA1c levels with no effects on body weight. Ebselen doubled β-cell mass, prevented apoptosis, prevented expression of oxidative stress markers, and enhanced intranuclear localization of pancreatic and duodenal homeobox (Pdx)-1 and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), two critical insulin transcription factors. Minimal β-cell replication was observed in both groups. These findings indicate that prevention of oxidative stress is the mechanism whereby ebselen prevents apoptosis and preserves intranuclear Pdx-1 and MafA, which, in turn, is a likely explanation for the beneficial effects of ebselen on β-cell mass and function. Since ebselen is an oral antioxidant currently used in clinical trials, it is a novel therapeutic candidate to ameliorate fasting hyperglycemia and further deterioration of β-cell mass and function in humans undergoing the onset of type 2 diabetes.
authors.affiliation: Pacific Northwest Diabetes Research Institute and Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, Washington.
authors.forename: Jana
authors.initials: J
authors.lastname: Mahadevan
authors.forename: Susan
authors.initials: S
authors.lastname: Parazzoli
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Oseid
authors.forename: Ann V
authors.initials: AV
authors.lastname: Hertzel
authors.forename: David A
authors.initials: DA
authors.lastname: Bernlohr
authors.forename: Sara N
authors.initials: SN
authors.lastname: Vallerie
authors.forename: Chang-qin
authors.initials: CQ
authors.lastname: Liu
authors.forename: Melissa
authors.initials: M
authors.lastname: Lopez
authors.forename: Jamie S
authors.initials: JS
authors.lastname: Harmon
authors.forename: R Paul
authors.initials: RP
authors.lastname: Robertson
mesh_terms: D017667:Adipocytes; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001393:Azoles / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight; D002454:Cell Differentiation; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D005979:Glutathione Peroxidase / Q000187:drug effects*; D006442:Glycated Hemoglobin / Q000187:drug effects; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D054833:Isoindoles; D037181:Lectins, C-Type / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects; D016566:Organoselenium Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000975:Antioxidants; D001393:Azoles; D001786:Blood Glucose; D005979:Glutathione Peroxidase; D006442:Glycated Hemoglobin; D054833:Isoindoles; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D016566:Organoselenium Compounds; D000094765:Glutathione Peroxidase GPX1; C094696:Klrg1 protein, rat; C042986:ebselen; C000722069:Gpx1 protein, rat